Recent studies on autoimmune diseases suggest that genetic factors in combination with environmental stimuli may play a role in activating aberrant autoimmune responses. The T lymphocyte, which is normally tolerant to self tissues, is thought to be the primary cells involved in promoting persistent autoimmune responses in many diseases such as rheumatoid arthritis, multiple sclerosis, insulin-dependent diabetes mellitus, and systemic lupus erythematosus. Whatever the initial cause, abnormalities in the tolerance of T cells for self antigens may play an important role in the pathogenesis of these diseases. The purpose of this proposal is to examine mechanisms involved in regulating peripheral T cell tolerance. Recent studies have demonstrated that the T cell is susceptible to exquisite regulation depending upon the microenvironment and more importantly the antigen presenting cell (or accessory cell) involved in initiating and promoting T cell responses. Studies from this laboratory have demonstrated that mitogenic stimuli that normally activate resting human peripheral blood T cells can induce a long-lasting state of nonresponsiveness when the cells are exposed to the stimulus in the absence of the appropriate accessory cell signals. The proposed study will define the cell surface molecules involved in interactions of T cells with accessory cells that are required for a positive response, as well as characterize the interactions that lead to the state of tolerance. In addition, one of the major effects of anergy-induction is defective IL2 production when T cells are restimulated with appropriate antigen or mitogen. These studies will attempt to determine the molecular basis for the defect in IL2 production in tolerized T cells. It is anticipated that new information will emerge from these studies that should provide new insights into the cellular and molecular basis for peripheral anergy of human T cells.